Variants in HNRNPH1 are associated with high myopia in humans and ocular coloboma in zebrafish

High myopia is one of the most common causes for blindness due to its associated complications. Genetic factor has been considered as the major cause for early-onset high myopia (eoHM), but exact genetic defects for most eoHM are yet to be identified. Through multi-step bioinformatics analysis of our in-house whole exome sequencing dataset from 5310 individuals, variants from 653 probands with eoHM were further compared with those from in-house controls as well as gnomAD database. The results showed that loss-of-function (LoF) variants in a novel gene HNRNPH1 were identified in two of 653 probands with eoHM but in none of 4657 probands with other eye conditions (P = 0.015). LoF variants in HNRNPH1 were extremely rare and intolerant, while two LoF variants in 653 eoHM were statistically higher than their frequency in gnomAD (P = 1.09×10-3). These two LoF variants, c.2dupT/p.? and c.121dup/p.(Q41Pfs*20), were absent from existing database. Variants in HNRNPH1 have not been associated with any inherited eye disease before. Expression of HNRNPH1 was enriched in ganglion cell layer and inner nuclear layer in humans. Knockdown of hnrnph1 in zebrafish resulted in ocular coloboma. All these suggests that HNRNPH1 supports its potential contribution to eoHM when mutated.